Abstract The sense of touch allows us to perceive and respond to the physical world ?we recognize objects held in our hands, discriminate between different textures and shapes, and sensory-motor feedback circuits coordinate our body movements. The sense of touch also underlies forms of social exchange and is thus an essential component of the human experience. The first step leading to touch perception is activation of a group of cutaneous sensory neurons called low- threshold mechanoreceptors (LTMRs). There are several LTMR types, and each has a unique sensitivity, morphology, physiological property and, presumably, function. Understanding the unique functions of each LTMR type, and how ensembles of LTMR activities are integrated and processed in the CNS to form touch percepts are outstanding questions in the field. Therefore, the overall goals of my laboratory, and thus this R35 proposal, are: 1) to elucidate the sensitivities, mechanisms of excitation, and unique functions of the major classes of mammalian cutaneous LTMRs; 2) to define the logic of LTMR circuit organization in the spinal cord and brainstem, and the nature of ascending pathways to the brain that underlie discriminative and affective touch perception; 3) to establish how the peripheral somatosensory system assembles during development; and 4) to determine whether and how dysfunction of touch circuits and their development underlies tactile deficits in autism spectrum disorders and during neuropathic pain. We are achieving these goals using an array of powerful mouse molecular genetic tools, combined with sophisticated electrophysiological, anatomical, behavioral and developmental assays. Successful completion of this R35's goals will thus reveal mechanisms of somatosensory nervous system development and function, and spinal cord touch information processing underlying perception, under normal and disease conditions.